Improvements to Nasal Compositions and Method of Use Thereof

ABSTRACT

A nasal composition is provided comprising or consisting of a first composition part in the form of a liquid for nasal application to a patient in use, and a second composition part in the form of a powder for nasal application to the patient in use. The first and second composition parts are applied to the patient separately or together as required.

The present invention relates to improvements to nasal compositions andto a method of use thereof.

Although the following description refers almost exclusively to a nasaldecongestant composition and to a method of application thereof, it willbe appreciated by persons skilled in the art that the present inventioncan be used for any nasal composition used for any purpose.

Nasal administration for delivery of drugs to a patient for either localor systemic effect is known. Examples of common nasally delivered drugsare decongestants and allergy treatments. The drug compositions aretypically in the form of a liquid spray or drops containing at least onetherapeutically active agent that is applied via spraying or locatingdroplets into a user's nasal cavity using a suitable dispenser, such asa pipette or dropper.

The nasal cavity is covered with a thin mucosa that has a good bloodsupply. A drug molecule can be transferred quickly from the nasal cavityacross a single epithelial layer of the mucosa and directly into thesystemic blood circulation of the patient without hepatic and intestinalmetabolism. This allows the therapeutically active agent to have a rapideffect within the patient's body and provides an alternative route ofapplication to oral administration or other administration forms. Aproblem associated with nasal administration of drug compositions inliquid form is that the liquid can flow out of the nasal cavity of thepatient due to gravity and normal nasal clearance (i.e. via nasalsecretions or mucociliary action) before it is absorbed through thenasal mucosa.

In an attempt to overcome the abovementioned problem, initial studieshave been undertaken which show that application of a singlemucoadhesive pharmaceutical solution with a decongestant containedtherein have a greater and longer lasting effect in subjects withperennial allergic rhinitis than a standard commercially availabledecongestant solution without a mucoadhesive solution contained therein(Tzachev et al—Br J Clin Phamacol. January 2002: 53 (1):107-109—“Comparison of the clinical efficacy of standard andmucoadhesive based nasal decongestants). However, the development of anyfixed formulation drug and mucoadhesive carrier is likely to be bothexpensive and time consuming. There is therefore still a need to developa commercially available nasal composition that overcomes the problemsof the prior art.

It is therefore an aim of the present invention to provide an improvednasal composition.

It is an aim of the present invention to provide a method of using animproved nasal composition.

It is a yet further aim of the present invention to provide acombination therapy for nasal application and a method of use thereof

It is a yet further aim of the present invention to provide a kit ofparts for a nasal composition and a method of use thereof.

According to a first aspect of the present invention there is provided anasal composition, said nasal composition comprising or consisting of afirst composition part in the form of a liquid for nasal application toa patient in use, and a second composition part in the form of a powderfor nasal application to the patient in use, said first and secondcomposition parts applied to the patient separately or together asrequired.

The applicants have found that provision of the second powdercomposition part prolongs the contact time of the first liquidcomposition part in the nasal cavity with the nasal mucosa, therebyincreasing the efficiency of the transfer of the liquid across the nasalmucosa in use. This in turn increases the efficacy of any agent ortherapeutic agent that may be contained within the first liquidcomposition part. The method of action of the composition parts isthought to be as a result of the second powder composition part slowingdown the clearance of the first liquid composition part due to thecreation of weak and/or temporary bonds between one or more componentsof the first and second composition parts and/or between one or morecomponents of the first and second composition parts and the nasalmucosa.

Thus, in one embodiment the second composition part is provided at sucha dose, timing between delivery of the first and second compositionparts and/or arrangement of the first and second composition parts sothat the second composition part improves the mucoadhesive action of thefirst composition part relative to if the first composition part isgiven on its own.

Preferably alteration of the grade and/or concentration of the secondcomposition part can be used to alter the mucoadhesive action of thefirst composition part, thereby making the clearance of the first liquidcomposition part from the nasal cavity relatively faster or slower.

In one embodiment the first liquid composition part includes or consistsof any or any combination of one or more therapeutically active agents,a drug, a steroid, pharmaceutical product, decongestant, allergy therapyagent, herbal agent, homeopathic agent, food supplement, probiotic,airway dilator and/or the like.

Non-limiting examples of decongestants and non-limiting examples of theconcentrations of the same that can be used for the first liquidcomposition part include Xylometazoline (i.e. 0.05% w/w), Oxymetazoline(i.e. 0.025-0.05% w/w) and/or the like.

An example of an anti-histamine that can be used for the first liquidcomposition part is Azelastine (and non-limiting examples of theconcentration are 0.1% or 0.15% w/w) and/or the like.

Non-limiting examples of nasal steroids that can be used for the firstliquid composition part include Mometasone furoate (and a non-limitingexample of the concentration is 0.05% w/w), Fluticasone propionate (anda non-limiting example of the concentration is 88 mcg-440 mcg per dose),Fluticasone Furoate (and a non-limiting example of the concentration is88 mcg-440 mcg per dose).

An example of an antimuscarinic that can be used for the first liquidcomposition part includes Ipratropium bromide (and a non-limitingexample of the concentration is 34-500 mcg per dose).

An example of a combination anti-histamine and nasal steroid that can beused for the first liquid composition part includes Azelastine andFluticasone propionate.

The dosages of the first liquid composition part are typically as perthe recommended drug use guidelines for the patient in question and thedisease state and/or condition being treated.

The first liquid composition part can be applied to the nasal cavity ofa patient in the form of a liquid spray or as droplets using a suitablenasal dispenser, such as for example a nasal spray dispenser, a nasalpipette, nasal dropper and/or the like.

The second powder composition part can be applied to the nasal cavity ofa patient as a result of a user inhaling the nasal powder using asuitable nasal dispenser, such as for example a squeeze bottle and/orthe like. An example of a possible nasal applicator for the powdercomposition is disclosed in EP1368090, incorporated herein by reference.The powder dispenser typically includes a deformable bottle containingthe powdered composition and which houses a dip tube. Application of asqueezing force on the sides of the bottle, using opposing fingers of auser, increases the internal pressure of the bottle when compared toatmospheric pressure. This results in an airflow that is channelled outof the bottle through the dip tube. This airflow entrains powderedmaterial, releasing a restricted amount of the powdered material fromthe bottle.

Preferably the dispensing apparatus of the first and/or secondcomposition parts dispenses a pre-defined dosage of liquid and powderrespectively, thereby controlling the dosage of the composition parts tothe user.

Preferably the dosage of the first and/or second composition parts arepharmaceutically effective and/or acceptable dosages.

In one embodiment the second powder composition part includes orconsists of any or any combination of cellulose powder,Hydroxypropylmethylcellulose (HPMC) powder, one or more therapeuticallyactive agents, pharmaceutical agents, steroid, drug, signalling agents,airway dilator agents, herbal agents, homeopathic agent, probiotics,food supplements and/or the like, such as for example any or anycombination of a drug, decongestant, allergy therapy agent and/or thelike. It can also contain a specific catalyst and/or an enhancer of apro-drug contained in the first liquid composition.

Preferably the HPMC is a dry powder and is typically inert.

The term “therapeutically active agent” used herein is typically anyactive substance suitable for nasal administration or its inactivepro-drug to be subsequently activated.

The term “homeopathic” or “herbal” are used herein to refer to productsderived from natural plant or mineral sources.

In one embodiment the therapeutic, homeopathic and/or herbal agent mayhave one or more of the following properties: antibacterial, antifungal,antiviral, antibiotic, immunomodulating, anti-inflammatory,anti-insomnia, cognitive enhancing or properties that affectcardiovascular function and/or the like.

Specific therapeutically active agents may include any or anycombination of: aspirin, isoprenosine, acyclovir, St. John's Wort,valerian extract, ginkgo biloba extract, Vitamins, garlic, lime ginger,ellagic acid, Echinacea, Swedish flower pollen, black walnut hulls,lemongrass, wormwood, grapefruit seed extract, broccoli, digestiveenzymes, hyaluronic acid, astralgus, rosehips, gentian, hypericum, horsechesnut, ginseng, green tea, phosphatidyl serine, phosphatidyl choline,citrus, pycnogenol, caffeine, quercitin, co-enzyme Q10, yarrow, teatree, noni juice, lipase, fructo-oligosaccharide, inulin, black cumin orallicin, any mint variety, turmeric and/or the like.

The term “pharmaceutical agent” as used herein refers to an agentavailable only under prescription or that requires efficacy, toxicityand marketing approval from the Medicines and Healthcare ProductsRegulatory Agency before use.

In one embodiment the second composition part includes or consists ofhydroxymethylcellulose (HPMC), an inert cellulose powder and/or thelike. The HPMC or cellulose powder remains as a powder until it entersthe patient's nasal cavity wherein it immediately turns to a gel likematerial on administration as it reacts with moisture present in thenasal tract.

In one embodiment the second composition part includes or consists of acellulose powder with or without the presence of one or more otheragents, therapeutically active agents, signalling agents, airway dilatoragents, a specific catalyst and/or enhancer of a pro-drug contained inthe first liquid composition and/or the like.

Preferably the second composition part includes or consists of asignificant proportion of cellulose powder or HPMC powder therein.Further preferably the second composition part comprises at least 50%HPMC or cellulose powder, preferably at least 60, 70, 80, 90, 95, 97 or99% HPMC or cellulose powder by total weight of the second compositionpart.

Preferably the dosage of the second composition part is between about 1mg-10 mg per nostril of a patient. Further preferably the dosage isbetween about 2.5 mg-7.5 mg, between about 3-7 mg, between about 4-6 mg,or about 5 mg per nostril of a patient.

The first and/or second composition part is typically given over suchtime scales as recommended by a medical practitioner and/or until thecondition being treated as been eradicated.

In one embodiment the second composition part is a HPMC powdercomposition as set out in EP1824450, incorporated herein by reference.

The HPMC or cellulose powder has a viscosity of approximately 10-20 Pa·s(Pascal Second) in a 2% aqueous solution at 20° C., preferablyapproximately 13-17 Pa·s, more preferably 14-16 Pa·s and most preferably15Pa·s. The viscosity is typically measured using a Ubbelohdeviscometer.

Preferably the second composition is of a type sold under the brand nameof NASALEZE®, NoAL®, NASAVAL, BOOTS ALLERGY BARRIER, ALERBLOCK, or othernames as licensed by brand owners Nasaleze International Ltd. Productsunder these brand name are conventionally used as isolators to isolatecontaminants and germs and prevent the same from entering the nasalmucosa of a patient. In the present invention the products are beingused in a novel manner as sealants to seal a liquid applied to the nasalcavity before or after administration of the same.

In one embodiment the second composition part includes any or anycombination of kali bichromium; a thickening agent such as gum orstarch; a disintegrant, such as sodium glycolate or cross linkedpovidone, a release agent such as magnesium stearate; an emulsifyingagent, a surfactant, anti-caking agents, granulating agentspreservatives, colourants and/or the like.

In one embodiment the second composition part includes a signalling orflavouring agent that can provide the patient with a pleasant sensoryfeedback upon use, which allows the patient to recognise thatadministration of the second composition part has taken place. Thesignalling agent can include any or any combination of mint, menthol,spearmint, any mint variety, turmeric, lemon, lime, peppermint,eucalyptus, lavender, citrus, strawberry, capsaicin and/or the like.

In one embodiment the signalling agent comprises up to 50% of the secondcomposition part, preferably up to 40%, 30%, 20%, 10%, 5%, 2%, 1%, 0.5%or 0.25% by total weight of the second composition part.

In one embodiment the second composition part is administered to thepatient prior to or just prior to administration of the firstcomposition part.

In one embodiment the first composition part is administered to thepatient prior to or just prior to administration of the secondcomposition part.

In one embodiment the first composition part and the second compositionpart are administered simultaneously or substantially simultaneously.

Preferably the first and second composition parts, irrespective of theorder in which they are administered, are administered sequentially oneafter another, and preferably immediately after each other. Furtherpreferably the second composition part is administered last or second inthe sequence.

In one embodiment the first and second composition parts areadministered less than or equal to 5 minutes after each other;preferably less than or equal to 2 minutes after each other; furtherpreferably less than or equal to 1 minute after each other; and yetfurther preferably less than or equal to 30 seconds after each other, 20seconds, 10 seconds, 5 seconds, 1 second after each other.

In one embodiment the composition can include or consist of a thirdcomposition part and/or one or more further composition parts inaddition to the first and second composition parts. The third and/orfurther composition parts can be administered nasally in any requiredorder with the first and second composition parts, although it ispreferred that the second composition part is administered last in thesequence. The third and/or further composition parts can be administeredimmediately before, between or after the first and second compositionparts, a pre-determined time period thereafter, substantiallysimultaneously to and/or the like. An example of a third compositionpart that can be given in combination with a first composition part isuse of an anti-histamine with a nasal corticosteroid, such as forexample, Azelastine and Fluticasone Propionate.

In one embodiment the composition consists of the first composition partand the second composition part to the exclusion of any othercomposition part.

In one embodiment the first composition part, the second compositionpart and/or the third and/or further composition parts are stand alone,independently applied, composition parts that are not mixed together orcome into contact with each other until application into the nasalcavity of a patient.

The composition of the present invention could be used to provide alocal effect in the nasal tract of a patient or could be absorbed intothe blood stream and used to provide a systemic effect in a patient asrequired.

According to one independent aspect of the present invention there isprovided a nasal composition, said nasal composition comprising a firstcomposition part for nasal application to a patient in use, and at leasta second composition part for nasal application to a patient in use,said first and second composition parts applied separately or togetheras required, the second composition part arranged so as to increase themucoadhesion of the one or more components of the first composition withthe nasal mucosa of a patient in use.

Preferably the first composition part is in the form of a liquid.

Preferably the second composition part is in the form of a powder.

According to one aspect of the present invention there is provided acombined nasal therapy, said combined nasal therapy comprising a firstcomposition part in the form of a liquid for nasal application to apatient in use, and a second composition part in the form of a powderfor nasal application to a patient in use, said first and secondcomposition parts applied separately or together as required.

According to one aspect of the present invention there is provided a kitof parts for a nasal composition, said kit of parts comprising a firstcomposition part in the form of a liquid for nasal application to apatient in use, and a second composition part in the form of a powderfor nasal application to a patient in use, said first and secondcomposition parts applied separately or together as required.

According to one aspect of the present invention there is provided amethod of treating a patient with a nasal composition. The treatment canbe effective for the diseases relating to the respiratory tract,allergic ailments, rhinitis, the upper respiratory tract, the lowerrespiratory tract of a patient, as a decongestant, rhinovirus, commoncold and/or the like.

According to one aspect of the present invention there is provided acomposition for the manufacture of a medicament for the treatment of adisease or illness relating to the respiratory tract, allergic ailments,rhinitis, the upper respiratory tract, the lower respiratory tract of apatient, said nasal composition comprising or consisting of a firstcomposition part in the form of a liquid for nasal application to apatient in use, and a second composition part in the form of a powderfor nasal application to the patient in use, said first and secondcomposition parts applied to the patient separately or together asrequired.

An embodiment of the present invention will now be described withreference to the accompanying figures, wherein:

FIGS. 1a and 1b shows a cross sectional pictorial view taken through apatient's nasal cavity and upper respiratory tract 1 illustrating postuse of AFRIN® only (distributed by Merck Consume Care, Inc) with thedecongestant active agent Oxymethazoline contained therein, shown byreference 2, and post use of AFRIN®+NoAL® (supplied by Nasaleze Ltd) incombination, shown by reference 4 respectively. The darker shading ofreference 4 shows a sealant effect created by use of the NoAL® incombination with the AFRIN® compared to the use of AFRIN® alone;

FIG. 2 shows a simplified illustration of a study design undertaken toshow the effects of 40 patients used in the clinical study;

FIG. 3 shows a simplified illustration of the age and genderdistribution of patients used in the clinical study shown in FIG. 2;

FIG. 4 is a graph showing the baseline peak expiratory nasal flow (PNIF)(L/min) values at days 1, 8 and 15 of the study;

FIG. 5 is a graph showing the peak expiratory nasal flow (PNIF) (L/min)values following insufflation of oxymetazoline on A. day 1 and B. day 8;

FIG. 6 shows the nasal itch/sneezing VAS scores on days 1, 8 and 15 ofthe study;

A one centre clinical study was undertaken to determine theeffectiveness of a nasal composition which is based on the sequentialapplication of two commercially available composition parts. The firstcomposition part is in the form of an existing commercially availablenon-adhesive decongestant liquid formulation and the second compositionpart is in the form of an existing commercially available cellulosecontaining powder to determine if the second composition part can “seal”the non-adhesive decongestant formulation in place within the nasalcavity of a patient.

The proposed mode of operation of the cellulose containing powder isthat upon contact of the cellulose containing powder with the nasalmucosa of a patient, the powder converts into an adhesive gel, whichslows down the nasal clearance of the first composition part withsubsequent enhancement of the therapeutically active decongestant agentcontained in the first composition part.

Method

The first composition part used was a decongestant liquid product calledAFRIN® (distributed by Merck Consume Care, Inc) with the decongestantactive agent Oxymethazoline 0.05% contained therein. The secondcomposition part used was a micronized methylcellulose powder calledNoAL (supplied by Nasaleze Ltd), licensed for the treatment of allergicrhinitis. The first and second composition parts were administered bythe patient into their nasal cavity immediately after each other. Thedosage regime was 1 puff/squirt of AFRIN immediately followed by 1puff/squirt of NoAL once a day for 7 days and then only.

The double-blind, randomised, placebo-controlled study contained 40patients suffering from moderately severe to severe perennial allergicrhinitis, with prominent nasal congestion. Defective nasal barrierfunction is implicated in allergic rhinitis, resulting in persistentinflammation and clinical symptoms, among which nasal congestion plays aprominent role. The study was performed out of the pollen season,between November and January. Inclusion criteria also included apositive skin prick test (wheal>3 mm diameter) to at least one of apanel of perennial allergens. Exclusion criteria encompassed individualswith seasonal allergic rhinitis or nasal polyposis; patients withserious chronic co-morbidities; with flu-like symptoms during the past30 days; pregnant or lactating women and individuals unable to giveinformed consent were excluded.

Half of the patients (20 patients) were selected at random foradministration of a Group 1 composition, which was the administration ofthe AFRIN (Oxymetazoline nasal spray, 0.05%) and the NoAL(cellulose/HPMC powder), and half of the patients (20 patients) wereselected at random for administration of a Group 2 composition, whichwas the administration of the AFRIN (Oxymetazoline) and a placebo in theform of a lactose powder, as shown in FIG. 2. The group 1 and group 2compositions were administered to the patients on day 1 and the patientswere tested on day 1 after administration of the composition, at day 8and at day 15. The group 1 and group 2 compositions were administeredregularly on a daily basis between day 1 and day 8 by the patient.Rescue medications only were prescribed to the patients between day 8and day 15 with the placebo and Oxymetazoline and NoAL no longer given.

Of the patients used in the study, 10 of the group 1 patients were maleand 10 of the group 1 patients were female; 7 of the group 2 patientswere male and 13 of the group 2 patients were female. The age range ofthe group 1 patients was 18-49 years old, with a mean age of 36 yearsand a median age of 36 years. The age range of the group 2 patients was21-48 years old, with a mean age of 33 years and a median age of 33years, as shown in FIG. 3.

The parameters measured in the study for each patient at day 1, 8 and 15included peak expiratory nasal flow (PNIF) using PNIF meters (In-CheckNasal, Clement Clarke International Ltd, Harlow, Essex, UK) which is ameasure of respiratory function; a saccharine test; and subjectivesymptoms were measured using a visual-analogue scale (VAS) and usingsymptom scores of 0-3 in diaries. Overall discomfort due to allergicrhinitis symptoms were recorded during visits on a 10 cm VAS rangingfrom “no nasal symptoms” at 0 cm to “worst nasal symptoms” at 10 cm.Patients also rated their stuffiness, rhinorrhea, itching and sneezingby a symptom score between 0 (none) and 3 (worst). From this, the totalnasal symptom score (TNSS) was calculated. The PNIF, L/min was measuredon day 1 immediately before drug administration and at minutes 1, 5, 15,30, 60, 120, 180, 240, 300 and 360 thereafter and the areas under thecurve were analyzed. Similar measurements of PNIF were made on day 8,and a single measurement was taken on day 15. The saccharine test is ameasure of nasal mucociliary clearance and involves placing a smallparticle of saccharine approximately 1 cm behind the anterior end of theinferior turbinate. In the presence of normal mucociliary action, thesaccharin will be swept backwards to the patient's nasapharynx and asweet taste is perceived by the patient. Failure of the patient todetect a sweet taste within 10-20 minutes signifies delayed mucociliaryclearance.

Statistical Analyses

PNIF values were distributed normally and differences within groupsanalysed using Student's t-test for paired data and between groupsStudent's t-test for unpaired data. As the number of times patientsresorted to rescue medication was not normally distributed, theseresults were given as median (25-75% range) and group differencesassessed using the Mann-Whitney U test. All tests were two tailed andthe threshold for statistical significance was set to P<0.05.

Results

Out of the 40 patients recruited in to the study, 2 dropped out from thetest treatment group, 1 for non-compliance and the other for a headache;and 2 dropped out from the placebo group, 1 for concomitant disease andthe other for a severe reaction to a cat. The remaining 36 patientscompleted all 3 visits and were included in the final analysis.

FIG. 4 shows a graph of the mean PNIF values at the start of the study(day 1), after 7 days treatment with HPMC powder or placebo (day 8) andafter a further 7 days of only rescue medication (day 15). Each groupcontains results from 18 individuals. Significance values werecalculated using Student's t-test for paired data. * indicated that thebaseline PNIF of the HPMC treated patients at day 15 were significantly(P=0.014) greater than that of the placebo treated patients. The valuewas calculated using Student's t-test for unpaired data.

The results in the HPMC group showed a 26% (P<0.001) in PNIF at day 8and a further 21% increase P<0.001) at day 15. The total increase inPNIF between days 1 and 15 was 53% (P<0.001). In the placebo group therewas a 24% in PNIF (P<0.001) at day 8 but no further increase at day 15.There was no significant difference between groups on days 1 and 8, butthe PNIF of the HPMC group was 26% greater (P=0.014) than that of theplacebo group on day 15.

FIG. 5 shows the PNIF values following insufflation of oxymetazoline onA. day 1 and B. day 8. The dots are the HPMC treated patients and thedots with a cross are the placebo group. Each group contains resultsfrom 18 individuals. Significance values were calculated using Student'st-test for unpaired data. On both days the effects of oxymetazoline weregreater in patients also inhaling HPMC compared with the placebo group.On day 1, the area under the curve (AUC) for the 360 minutes ofobservations for oxymetazoline was 20% greater in patients receivingHPMC compared with those receiving the placebo (56,366+/−14,910L.min/min vs 46,818+/−12,080 L.min/min, P=0.042). On day 8 AUC foroxymetazoline was 23% greater in the HPMC group than the placebo(60,855+/−13691 L.min/min vs 49,350+/−11211 L.min/min, P=0,009).

FIG. 6 shows the nasal itch/sneezing VAS scores on day 1, 8 and 15 ofthe study. The darkly shaded dots are the Placebo treated patients andthe lightly shaded dots at the HPMC treated patients. Each groupcontains results from 18 individuals. Significance values werecalculated using Student's t-test for paired data. There were nostatistically significant differences between groups.

The VAS assessments by patients on days 1, 8 and 15 of nasal congestion,rhinorrhea, itching/sneezing and total nasal symptoms are shown inTable 1. In the placebo group, there were significant improvements innasal congestion, rhinorrhea and total nasal symptoms at day 8 butlittle or no further improvement thereafter. In the HPMC treated groupthere were similar improvements in these parameters at day 8. However,in this group these improvements appeared to continue up to day 15. Withtotal nasal symptoms the improvement between days 8 and 15 wasstatistically significant (P=0.006). There were no statisticallysignificant differences between groups. A similar pattern of results wasobtained from analysis of patients' diaries on days 1, 8 and 15 of thestudy.

Of special mention is nasal itching/sneezing. With this symptom therewas no significant improvement in the placebo group. However, in theHPMC treated group there were significant improvements of 56% (P=0.012)and 74% (P=0.013) at days 8 and 15 respectively. Also, the improvementbetween days 8 and 15 was statistically significant (P=0.02). However,the differences between the treatment groups failed to reachstatistically significance, mainly because of the numbers of patientsgiving low itch/sneezing scores at all times (see FIG. 6).

The median (with 25 and 75% range) numbers of times patients resorted toescape medication, puffs of oxymetazoline, during days 8-15 of the studywere 8.5 (1-15.5) for the HPMC group and 16 (11.5-16) for the placebogroup. There was a wide variability between the patients which precludedthe difference between groups being statistically significant (P=0.076).However, 13 of the 18 patients who received the placebo on days 1-7 tookmore than 2 puffs of oxymetazoline per day compared with only 5 HPMCtreated patients (P=0.04, Fisher's exact test).

The conclusions of the study showed that use of micronizedmethylcellulose powder (HPMC) enhanced the decongestant effect of nasaloxymetazoline in patients with perennial allergic rhinitis. One week ofregular treatment with nasal oxymetazoline and HPMC augmented the nasalpatency and this effect carried over for at least one further week afterits discontinuation. This carry over effect may be as a result of theHPMC augmenting the mucosal barrier in allergic rhinitis.

The Applicants hypothesise that there are two possible mechanisms bywhich HPMC may act to enhance the effects of oxymetazoline therapy. Thefirst is a purely physical one. As HPMC was insufflated immediatelyafter oxymetazoline, the formation of a gel layer above the decongestantwould be likely to reduce its clearance from the nasal mucosa andthereby increase its effectiveness. Such effect would occur even withthe first dose as was seen on day 1 of the study. The second mechanismwould be for HPMC to create an improved barrier to allergen penetrationinto the nasal mucosa. In the longer term, it would reduce theinflammatory events of the mucosal barrier thereby reducing nasalreactivity. The activity is evidenced particularly by the increasedbaseline PNIF, an index of nasal congestion, up to 15 days in the HPMCtreated group.

Although the study was undertaken only in respect of patients sufferingfrom perennial allergic rhinitis, the results of the study suggest thata similar effect could be found in patients suffering from otherrespiratory and/or allergy complaints.

1. A nasal composition, said nasal composition comprising or consistingof a first composition part in the form of a liquid for nasalapplication to a patient in use, and a second composition part in theform of a powder for nasal application to the patient in use, said firstand second composition parts applied to the patient separately ortogether as required.
 2. A nasal composition according to claim 1wherein the first liquid composition part includes or consists of any orany combination of one or more therapeutically active agents, a drug,pharmaceutical product, decongestant, allergy therapy agent, herbalagent, homeopathic agent, food supplement, probiotic or airway dilator,and the second powder composition part includes or consists of any orany combination of cellulose powder, hydroxymethylcellulose (HPMC)powder, one or more therapeutically active agents, pharmaceutical agentsdrug, signalling agents, airway dilator agents, herbal agents,homeopathic agent, probiotics, food supplements, allergy therapy agent,decongestant, or a catalyst and/or an enhancer of a pro-drug containedin the first liquid composition part.
 3. A nasal composition accordingto claim 1 wherein the first liquid composition part is applied to thenasal cavity of the patient in the form of a liquid spray or as dropletsusing a suitable nasal dispenser, and the second powder composition isapplied to the nasal cavity via nasal inhalation by a patient. 4.(canceled)
 5. (canceled)
 6. A nasal composition according to claim 2wherein the therapeutic, homeopathic and/or herbal agent includes one ormore of the following properties: antibacterial, antifungal, antiviral,antibiotic, immunomodulating, anti-inflammatory, anti-insomnia,cognitive enhancing or properties that affect cardiovascular function.7. A nasal composition according to claim 2 wherein the therapeuticallyactive agent includes any or any combination of aspirin, isoprenosine,acyclovir, St. John's Wort, valerian extract, ginkgo biloba extract,Vitamins, garlic, lime ginger, ellagic acid, Echinacea, Swedish flowerpollen, black walnut hulls, lemongrass, wormwood, grapefruit seedextract, broccoli, digestive enzymes, hyaluronic acid, astralgus,rosehips, gentian, hypericum, horse chesnut, ginseng, green tea,phosphatidyl serine, phosphatidyl choline, citrus, pycnogenol, caffeine,quercitin, co-enzyme Q10, yarrow, tea tree, noni juice, lipase,fructo-oligosaccharide, inulin, black cumin or allicin, any mintvariety, turmeric.
 8. A nasal composition according to claim 1 whereinthe second composition part includes a significant proportion ofcellulose powder or hydroxymethylcellulose (HPMC) powder therein,wherein the second composition part includes at least 50% HPMC orcellulose powder, or wherein the second composition part includes atleast 60, 70, 80, 90, 95 or 99% HPMC or cellulose powder by total weightof the second composition part.
 9. (canceled)
 10. (canceled)
 11. A nasalcomposition according to claim 1 wherein the dosage of the secondcomposition part is between 1 mg-10 mg per nostril of a patient, orwherein the dosage of the second composition part is between 2.5 mg-7.5mg, between 3-7 mg, between 4-6 mg or between 5 mg per nostril of apatient.
 12. (canceled)
 13. A nasal composition according to claim 1wherein the second composition part includes or consists of cellulosepowder or hydroxymethylcellulose (HPMC) powder, and said powder has aviscosity of 10-20 Pa·s in a 2% aqueous solution at 20° C., or whereinthe powder has a viscosity of 13-17 Pa·s, 14-16 Pa·s or 15 Pa·s. 14.(canceled)
 15. A nasal composition according to claim 1 wherein thesecond composition part includes any or any combination of kalibichromium; a thickening agent, gum, starch; a disintegrant, sodiumglycolate, a cross linked povidone, a release agent, magnesium stearate;an emulsifying agent, a surfactant, anti-caking agents, granulatingagents preservatives or colourant, a signalling or flavouring agent thatcan provide the patient with a pleasant sensory feedback upon use. 16.(canceled)
 17. A nasal composition according to claim 9 wherein thesignalling agent includes any or any combination of mint, menthol,spearmint, any mint variety, turmeric, lemon, lime, peppermint,eucalyptus, strawberry, lavender, citrus or capsaicin.
 18. A nasalcomposition according to claim 16 wherein the signalling agent comprisesup to 50% of the second composition part, or wherein the signallingagent comprises up to 40%, 30%, 20%, 10%, 5%, 2% 1%, 0.5% or 0.25% bytotal weight of the second composition part.
 19. (canceled)
 20. A nasalcomposition according to claim 1 wherein the second composition part isadministered to the patient prior to or just prior to administration ofthe first composition part to the patient, wherein the first compositionpart is administered prior to or just prior to administration of thesecond composition part to the patient, wherein the first compositionpart and the second composition part are administered simultaneously orsubstantially simultaneously, or wherein the first composition part andthe second composition part, irrespective of the order in which they areadministered, are administered sequentially one after another. 21.(canceled)
 22. (canceled)
 23. (canceled)
 24. A nasal compositionaccording to claim 1 wherein the first and second composition parts areadministered less than or equal to 5 minutes after each other, orwherein the first and second composition parts are administered lessthan or equal to 2 minutes after each other less than or equal to 1minute after each other, less than or equal to 30 seconds after eachother, 20 seconds after each other, 10 seconds after each other, 5seconds after each other or 1 second after each other.
 25. (canceled)26. A nasal composition according to claim 1 including or consisting ofa third composition part and/or further composition part, wherein thefirst, second, third and/or further composition parts are stand alone,independently applied, composition parts that are not mixed together orcome into contact with each other until application into the nasalcavity of a patient.
 27. (canceled)
 28. (canceled)
 29. (canceled)
 30. Anasal composition for the manufacture of a medicament for the treatmentof a disease relating to the respiratory tract, allergic ailment,rhinitis, the upper respiratory tract and/or the lower respiratory tractof a patient, said nasal composition comprising or consisting of a firstcomposition part in the form of a liquid for nasal application to apatient in use, and a second composition part in the form of a powderfor nasal application to the patient in use, said first and secondcomposition parts applied to the patient separately or together asrequired.